Thrap3 promotes R-loop resolution via interaction with methylated DDX5

Abstract

Transcription-replication conflicts lead to DNA damage and genomic instability, which are closely related to human diseases. A major source of these conflicts is the formation of R-loops, which consist of an RNA-DNA hybrid and a displaced single-stranded DNA. Although these structures have been studied, many aspects of R-loop biology and R-loop-mediated genome instability remain unclear. Here, we demonstrate that thyroid hormone receptor-associated protein 3 (Thrap3) plays a critical role in regulating R-loop resolution. In cancer cells, Thrap3 interacts with DEAD-box helicase 5 (DDX5) and localizes to R-loops. Arginine-mediated methylation of DDX5 is required for its interaction with Thrap3, and the Thrap3-DDX5 axis induces the recruitment of 5'-3' exoribonuclease 2 (XRN2) into R-loops. Loss of Thrap3 increases R-loop accumulation and DNA damage. These findings suggest that Thrap3 mediates resistance to cell death by preventing R-loop accumulation in cancer cells.

Cancer: DNA damage associated with nucleic acid loops A nuclear protein appears to inhibit cancer cell death by preventing the accumulation of nucleic acid structures called R-loops. R-loops are by-products of transcription, comprising two misaligned DNA strands and one RNA strand. They are involved in gene expression, but also threaten genome integrity and have been linked to the onset of neurodegeneration and cancers. A team led by Jang Hyun Choi and Hyug Moo Kwon, Ulsan National Institute of Science and Technology, South Korea, explored the role of Thrap3, a nuclear protein involved in RNA splicing, in R-loop-associated DNA damage. They found that Thrap3 binds to an enzyme essential for resolving R-loops. When the team suppressed Thrap3 expression, they saw an increase in R-loops in both normal and cancer cells. This R-loop accumulation significantly inhibited the growth of breast cancer cells.